Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20250014
Ned H Kalin
{"title":"New Developments in the Treatment of Depression, OCD, and Schizophrenia.","authors":"Ned H Kalin","doi":"10.1176/appi.ajp.20250014","DOIUrl":"https://doi.org/10.1176/appi.ajp.20250014","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"223-226"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-11DOI: 10.1176/appi.ajp.20240076
William P Horan, Colin Sauder, Philip D Harvey, Ian S Ramsay, Samantha E Yohn, Richard S E Keefe, Vicki G Davis, Steven M Paul, Stephen K Brannan
Objective: Xanomeline and trospium chloride (formerly known as KarXT), a novel M1/M4 muscarinic receptor agonist, demonstrated efficacy across phase 2 and 3 trials as monotherapy for the treatment of inpatients with acute schizophrenia on the Positive and Negative Syndrome Scale total score primary endpoint. In the phase 2 trial, xanomeline/trospium improved performance on a cognitive outcome measure in the subgroup of participants with clinically significant baseline cognitive impairment. The authors sought to confirm this finding using data from two phase 3 trials.
Methods: Data were pooled from two 5-week inpatient trials of xanomeline/trospium monotherapy in patients with acute schizophrenia. The statistical analysis plan prespecified comparisons of cognitive composite score changes between xanomeline/trospium and placebo in the full sample and the cognitively impaired (≤1 SD below norms at baseline) subgroup.
Results: There was no significant xanomeline/trospium effect in the full sample (N=357); however, in the impaired subgroup, xanomeline/trospium (N=71) had a significantly greater benefit for cognition compared with placebo (N=66; least squares mean difference=0.31, SE=0.10; d=0.54). The xanomeline/trospium effect size increased significantly with a more stringent baseline impairment threshold (≤-1.5 SD; d=0.80). Improvements in cognition were minimally correlated with concurrent changes in total, positive, and negative symptoms in both treatment groups.
Conclusions: Participants with acute schizophrenia with prespecified impairments demonstrated significant cognitive improvement with xanomeline/trospium compared with placebo. This result directly confirms earlier findings. This benefit is not attributable to changes in symptoms, despite substantial evidence of efficacy for psychosis. Evaluation of xanomeline/trospium's potential for cognitive enhancement in a well-controlled trial of stable patients with cognitive impairment is warranted.
{"title":"The Impact of Xanomeline and Trospium Chloride on Cognitive Impairment in Acute Schizophrenia: Replication in Pooled Data From Two Phase 3 Trials.","authors":"William P Horan, Colin Sauder, Philip D Harvey, Ian S Ramsay, Samantha E Yohn, Richard S E Keefe, Vicki G Davis, Steven M Paul, Stephen K Brannan","doi":"10.1176/appi.ajp.20240076","DOIUrl":"10.1176/appi.ajp.20240076","url":null,"abstract":"<p><strong>Objective: </strong>Xanomeline and trospium chloride (formerly known as KarXT), a novel M<sub>1</sub>/M<sub>4</sub> muscarinic receptor agonist, demonstrated efficacy across phase 2 and 3 trials as monotherapy for the treatment of inpatients with acute schizophrenia on the Positive and Negative Syndrome Scale total score primary endpoint. In the phase 2 trial, xanomeline/trospium improved performance on a cognitive outcome measure in the subgroup of participants with clinically significant baseline cognitive impairment. The authors sought to confirm this finding using data from two phase 3 trials.</p><p><strong>Methods: </strong>Data were pooled from two 5-week inpatient trials of xanomeline/trospium monotherapy in patients with acute schizophrenia. The statistical analysis plan prespecified comparisons of cognitive composite score changes between xanomeline/trospium and placebo in the full sample and the cognitively impaired (≤1 SD below norms at baseline) subgroup.</p><p><strong>Results: </strong>There was no significant xanomeline/trospium effect in the full sample (N=357); however, in the impaired subgroup, xanomeline/trospium (N=71) had a significantly greater benefit for cognition compared with placebo (N=66; least squares mean difference=0.31, SE=0.10; d=0.54). The xanomeline/trospium effect size increased significantly with a more stringent baseline impairment threshold (≤-1.5 SD; d=0.80). Improvements in cognition were minimally correlated with concurrent changes in total, positive, and negative symptoms in both treatment groups.</p><p><strong>Conclusions: </strong>Participants with acute schizophrenia with prespecified impairments demonstrated significant cognitive improvement with xanomeline/trospium compared with placebo. This result directly confirms earlier findings. This benefit is not attributable to changes in symptoms, despite substantial evidence of efficacy for psychosis. Evaluation of xanomeline/trospium's potential for cognitive enhancement in a well-controlled trial of stable patients with cognitive impairment is warranted.</p>","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":" ","pages":"297-306"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-15DOI: 10.1176/appi.ajp.20240378
Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura, Alan F Schatzberg, Carlos A Zarate, Michael Michaelides
Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an N-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.
{"title":"Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?","authors":"Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura, Alan F Schatzberg, Carlos A Zarate, Michael Michaelides","doi":"10.1176/appi.ajp.20240378","DOIUrl":"10.1176/appi.ajp.20240378","url":null,"abstract":"<p><p>Ketamine is a racemic compound and medication comprised of (<i>S</i>)-ketamine and (<i>R</i>)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.</p>","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":" ","pages":"247-258"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-02DOI: 10.1176/appi.ajp.20220785correction
{"title":"Correction to Deligiannidis et al.","authors":"","doi":"10.1176/appi.ajp.20220785correction","DOIUrl":"10.1176/appi.ajp.20220785correction","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":" ","pages":"311"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20241088
Andre R Brunoni, Frank Padberg
{"title":"Spaced Transcranial Direct Current Stimulation for Depression: The Road Less Traveled.","authors":"Andre R Brunoni, Frank Padberg","doi":"10.1176/appi.ajp.20241088","DOIUrl":"https://doi.org/10.1176/appi.ajp.20241088","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"231-233"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-02-19DOI: 10.1176/appi.ajp.20240181
Alexander McGirr, Jaeden Cole, Scott B Patten, Beverly Adams
{"title":"Intermittent Theta Burst Stimulation With Adjunctive D-Cycloserine for Obsessive-Compulsive Disorder: A Randomized Clinical Trial.","authors":"Alexander McGirr, Jaeden Cole, Scott B Patten, Beverly Adams","doi":"10.1176/appi.ajp.20240181","DOIUrl":"10.1176/appi.ajp.20240181","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":" ","pages":"307-311"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20241213
Dana E Díaz, Kate D Fitzgerald
{"title":"Beyond Feared Outcomes: Exploring Sensory Phenomena as a Novel Therapeutic Target for OCD.","authors":"Dana E Díaz, Kate D Fitzgerald","doi":"10.1176/appi.ajp.20241213","DOIUrl":"https://doi.org/10.1176/appi.ajp.20241213","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"234-236"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20241187
Daniel C Javitt
{"title":"Xanomeline-Trospium Treatment of Cognitive Impairments of Schizophrenia: Hope for Some, or Hope for All?","authors":"Daniel C Javitt","doi":"10.1176/appi.ajp.20241187","DOIUrl":"https://doi.org/10.1176/appi.ajp.20241187","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"237-239"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20241151
Joshua C Brown, Noah S Philip
{"title":"Pharmaco-Transcranial Magnetic Stimulation: Letting Mechanism Guide the Way.","authors":"Joshua C Brown, Noah S Philip","doi":"10.1176/appi.ajp.20241151","DOIUrl":"10.1176/appi.ajp.20241151","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"240-242"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1176/appi.ajp.20240121
Metten Somers, Floortje E Scheepers
{"title":"Irremediable Psychiatric Suffering, a Potential Indication for Psilocybin Treatment.","authors":"Metten Somers, Floortje E Scheepers","doi":"10.1176/appi.ajp.20240121","DOIUrl":"https://doi.org/10.1176/appi.ajp.20240121","url":null,"abstract":"","PeriodicalId":7656,"journal":{"name":"American Journal of Psychiatry","volume":"182 3","pages":"243-246"},"PeriodicalIF":15.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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